Oxido steroids



oxmo STEROIDS,

' Merck & Co., Inc., Rahway, N.J., a corporation of New Jersey .NoDrawing. Application October 1, 1958 Serial No. 764,513

2 Claims. (Cl. ecu-239.55

This invention relates to new steroids of the pregnane series and to processes of preparing such compounds' More specifically, it .Ielates to i6rsubstituted-l6nrmethylpregnanes and methods of preparing them. Still more specifically, it is concerned with 16a-methyl-17-20,20-21 bisrnethylepedioxy 3 ethylenedioxy 5a,6a oxido allopregnane, and with the synthesisof this substance from lfib eme'thyl substance S.

According to my invention the novel steroidsubstance 16 methyl l7 20,20 -;2: l bismethylenedioxy 3- ethyIenediQXY-Sa,6a{oxido:allopregnane is prepared from 160: methyl 4 pregn'err 3,20 -dione 17;2l diol (16a-I116ihyl substance S) by the sequence of reactions shown below:

The end product of this invention, Compound IV hereinabove, is a useful intermediate in the synthesis of physiologically active steroids as discussed more fully hereinbelow.

According to the first step of my new process, 16amethyl substance S is converted to a 16a-methyl-l7-20, 20-21 bismethylenedioxy steroid of Formula H hereinabove by treatment with formaldehyde. This reaction is preferably carried out in a two-phase solvent system wherein the steroid is dissolved in an organic solvent such as chloroform and the formaldehyde is present primarily in aqueous phase containing a mineral acid, preferably hydrochloric acid. The strong acid is necessary to the success of the reaction. In the succeeding step, a 160:- methyl 17 20,20 21 bismethylenedioxy 3 ethylenedioxy steroid is prepared by treating a compound of Formula H with ethylene glycol in the presence of an acid catalyst, preferably in the presence of a small amount of p-toluene sulfonic acid. Introduction of the 3-ethylenedioxy substituent is brought about in an organic solvent medium comprising an inert solvent such as benzene or toluene. The reaction is carried out for about -20 hours at the reflux temperature. I

In the third and final step of my invention, a 50:,6aoxido steroid of Formula IV hereinabove is' obtained by reacting a A -steroid of Formula III with a per-acid such,

as perbenzoic, peracetic or perthaliei Formation of the oxide is accomplished by intimately contacting the reactants in an inert solvent medium at about room temperature. When the reaction is complete, excess per-acid is decomposed by methods known in the art and the desired 16:): methyl 17 20,20 21 bismethylenedioxy 3,-'

ethylenedioxy-5a,6a-oxido-allopregnane recovered from the solvent by the usual methods.

The following examples are given for purposes of illustration and not by way of limitation:

EXAMPLE 1 16a-m'ethyl-17-20,20-21 bismthylenedioxy-4- pregnen-3-one EXAMPLE 2 16a-methyl-17-20,20-21 bismethylenedioxy-3-ethylenedioxy-S-pregnene One gram of 16a-methyl-17-20,20-21 bismethylenedioxy-4-pregnen-3-one is dissolved in 40 ml. of benzene. 2 ml. of ethylene glycol and 0.8 grams of p-toluene sulfonic acid are added and the resulting mixture refluxed for 16 hours. Water is continuously removed from the refluxing reaction mixture. The mixture is then cooled to 20 C., washed with three 10 ml. portions of water, 10 ml. of saturated sodium bicarbonate solution and again with 10 ml. of water. The benzene solution is separated, dried over magnesium sulfate and concentrated to dryness in vacuo. The solid is triturated with ether to give methyl 17 20,20 21 bismethylenedioxy 3 ethylenedioxy-S-pregnene which may be further purified by recrystallization from the acetonitrile.

EXAMPLE 3 1 6 u-m ethyl-1 7-20,20-21 bismethylenedioxy-3-elhylenedioxy-Su,6a-oxido-allapregnane One gram of 16a-methyl-17-20,20-21 bismethylenedioxy-3-ethylenedioxy-5-pregnene is added to 1.5 ml.,of

0.39 molar perbenzoic acid in benzene with cooling to maintain the temperature of 2025 C. The reaction mixture is held at 25 C. for 60 hours. At the end of this time it is treated with 15% sodium bisulfite solution and then with saturated sodium bicarbonate solution to remove any acid. The organic layer is separated and dried over sodium sulfate. It is then filtered and concentrated to dryness'underreduced pressure; The residual solid is crystallized from methanol to give substantially pure 16a-methyl-17-20,20-21 bismethylenedioxy 3-ethylenedioxy-5a,6a-oxido-allopregnane.

The 16or. 1 methyl 17 20,20-21, bismethylenedioxy-El:

ethylenedioxy-5u,6su-oxido allopregnane of this invention,

is useful vas fan important intermediate in synthesizing 6 a,l6a-dimethyl hydrocortisone, asubstance which has an unusually high degree of cortisone-like anti-inflammatory activity and which is thus useful in the treatment of arthritis and various dermatoses.

16u-methyll7-20,20-2l bismethylenedioxy-3 -ethylenedio y-Su,6ct-oxido-allopreguane is converted to 6a,16rx-d i-, methyl hydrocor'tisone by first reacting with, methyl magnesium bromide in ether or benzene at about 50 70 C. forv 5-6 hours to give 6,3,16m-dimethyl-l7-20,20 21, bismethylenedioxy-3.,-'ethylenedioxy allopregnan Sat-01;. This latter inaterial is then treated with 8% sulfuric "acid' in methanol to produce 6fi,16u-dimethyl-17-20,20-21 bis nie'thylenedioxy-allopregnan-3-one-5u ol which compound.

as well as the earlier steps in the process for converting the end product of this invention to 6a,l6-dimethyl hydrocortisone are discussed more fully and claimed in copending application of Sletzinger and Gaines, Serial No. 764,525, filed October 1, 1958.

lfia-methyl substance S which is employed as the starting material in the process of, this invention has been described in J.A.C.S. 80, 4431 (1958). Preparation of this material is also described in depending application Serial No. 754,181, filed August 11, 1958, now abandoned and in the copending continuation-impart application thereof.

Any departure from the above description which conforms to the present inventionis intended to be included within the scope of the claims.

- l. 16m-methyl-17-20,20-'2l"bisniethylenedioxy-ii-ethylenedioxy-Sa,6u-oxido-allopregnane.

2, lGu-methyl-17-2Q,20 Zl, hismethylenedioxy-3-ethylene i Y- -P s ene.

i v ikife'mi h file i h Patent UNITED T TES PATENTS 2,742,461 Bernstein et-al. Apr. 11, 1956 2,838,501 Campbell a a. June to, 1958 2,838,502 Beal a a! June 10, 1958 OTHER REFERENCES Beyler et al.; J.A.C.S. 1517-l8 (March 1958). 

1. 16A-METHYL-17-20,20-21 BISMETHYLENEDIOXY-3-ETHYLENEDIOXY-5A,6A-OXIDO-ALLOPREGNANE. 